Alfatradiol, also known as 17α-estradiol (17α-E2), is a naturally occurring enantiomer of 17β-estradiol which differs in stereochemistry at the 17th carbon atom. Unlike other exogenous estrogens, alfatradiol is considered a non-feminizing estrogen because it has a significantly reduced binding affinity for the estrogen receptors compared to 17β-estradiol.
17α-E2 is synthesized in the brain and has a higher binding affinity for the its brain receptor ER-X. Because 17α-E2 has neuroprotective properties, it is hypothesized that it could be used as a therapeutic agent for HIV-related neurocognitive disorders.
Mechanism of action
17α-E2 is thought to increase AMPK and reduce mTORC1 activity specifically in visceral adipose tissue but not in the liver or skeletal muscle, contrary to other interventions that usually have a system effect such as caloric restriction. In addition, 17α-E2 appears to have a highly sex-specific mode of action.
The beneficial effect of 17-α estradiol on male-specific life expectancy is associated with the fact that it suppresses the age-related increase in the activity of MAPK signaling pathways involved in male inflammatory processes. In addition, 17α-estradiol appears to protect males from age-related neuroinflammation of the hypothalamus, caused by age-related changes in the activity of the sex gonads. The study of this phenomenon is important for the field of longevity, since the hypothalamic-pituitary-testicular (HPT) axis plays an important role in the mechanisms of exceptional longevity in men. It should be noted that chronic treatment with standard doses of 17α-E2 does not adversely affect reproductive fitness in male mice.
Interestingly, rapamycin, acarbose and 17α-estradiol might share a common mechanism of action by regulating the ERK1/2 signalling pathway and the p38-MAPK pathway in both sexes, despite the lifespan and IGF1-specific effects of 17α-estradiol.
Effects on health and lifespan
Aging is associated to an increase in visceral adiposity, metabolic disorders and chronic inflammation. In this context, alfatradiol might be a useful therapeutic agent. Animal studies have shown that administration of 17α-E2 has anti-inflammatory effects and can reduce body weight, leading to a significant improvement in fasting insulin levels, glycated hemoglobin HbA1C and glucose tolerance.
Other studies have shown that alfatradiol leads to the production of hepatic insulin-like growth factor (IGF1) in male mice only, and can extend male lifespan by an average of 7% and a maximum of 19% when starting therapy from 16 months, but has no effect in the lifespan of females. When administered to elderly male mice (but not females or neutered males), it improved physical performance and age-related sarcopenia by increasing muscle mass and improving motor coordination.
Topical treatment with 17α-estradiol was also found to reduce androgenic hair loss in women, though it does not seem to be effective for growing new hair and this is currently its only medical use.
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